TWI625129B - New coated controlled release active agent carriers - Google Patents

Abstract

The present invention relates to a carrier for controlled release active agent comprising a core and a coating encapsulating the core, the core comprising a surface-reacted natural or synthetic calcium carbonate and at least one active agent, wherein the at least one active agent The surface is associated with a natural or synthetic calcium carbonate, and wherein the surface is reacted with natural or synthetic calcium carbonate as a reaction product of natural or synthetic calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is treated in situ by acid treatment Formed and/or supplied by external sources. Furthermore, it relates to the preparation of supported carriers and their use in different applications.

Description

Novel coated controlled release active agent carrier

This invention relates to a novel coated controlled release active agent carrier, a method of making the same, and uses thereof.

Controlled release formulations are generally known in the art, especially with regard to pharmaceutical formulations. Such formulations are, for example, formulated to slowly dissolve and release the drug over time to extend the effectiveness of the active agent. Sustained-release tablets are typically formulated such that the active ingredient is typically embedded in a matrix of insoluble materials, such as polyacrylic acid, such that the dissolved active agent must be routed through the pores in the matrix.

Alternatively, it is known to coat a coating that provides controlled release onto a formulation that would otherwise be released immediately. The coatings are typically selected from polymeric materials. A typical example thereof is a formulation for oral administration which is coated with an acid-resistant, alkali-soluble coating to ensure passage through the stomach without loss of the active agent, and the agent is subsequently released in an alkaline intestinal environment, or The loss of the pharmaceutical agent during processing is prevented, and the release of the pharmaceutically active substance is delayed beyond the disintegration of the rapidly disintegrating dosage form (e.g., in the mouth) as described in US 2009/0280172 A1.

In this regard, direct application of the active agent typically has considerable disadvantages. Thus, it is known from GB 1,409,468 that when fine particles are applied, the individual particles adhere to each other during coating and form larger cohesive polymers, even by coating the particles in the form of a fluidized bed or by coating with a thin coating. The solution can not be avoided, and it is known that the encapsulation technique requires convergence for the stability of the substance to be coated, because in the case of incompatibility between the solvent and the substance, in the process There is a risk of degradation during the period, or there is a risk of loss of the substance due to the solubility of the substance in the solvent. According to GB 1,409,468, this problem can be solved by the specific choice of solvent to dissolve the coating material.

Controlled-release formulations are suitable for pharmaceutical applications, but are also of interest in other fields, such as in paper, paint, agricultural, bio, cosmetic or any other technical applications, where it is important to release the active agent in a specific target environment. And unless it reaches this environment, it will not be released, or it needs to be extended for a certain period of time.

For example, controlled release formulations are also used to avoid the mixture of active agents reacting with each other prior to their application, as described by high efficiency encapsulated bleaching by coating several layers of coatings having different melting points and heat treating the encapsulated particles. U.S. Patent No. 4,657,784, the disclosure of which is incorporated herein by reference.

Thus, under certain conditions (eg depending on the temperature, pH or background in the target environment), controlled release may mean immediate release. In any application, a controlled release formulation should meet the following requirements: (i) maintain a sufficient amount of active agent prior to release in the target environment (ii) release a sufficient amount of active agent in the target environment, and (iii) target Adequate protection by the carrier prior to delivery and release in the environment maintains sufficient activity.

Meeting the above requirements is a high-demand issue in which a controlled release formulation must be selected depending on the nature of the active agent to be transported and the environment in which the active agent must be released or may have to be protected until it reaches the target environment.

Therefore, there is a continuing need for novel and improved vectors.

For example, a carrier for controlled release of a thermosensitive agent that degrades at certain temperatures should not only protect the active agent from harmful temperatures before reaching the target environment or before the release is completed, but should also be at a temperature low enough to cause degradation. The active agent is released underneath.

Accordingly, improved controlled release formulations should not only provide controlled release of the active agent as a whole, but should also reliably transfer the active agent to the target environment even under conditions which are detrimental to the active agent or conventional coating materials, and should be readily Obtained and processed.

For example, WO 2010/121619 A1 and WO 2010/121620 A1 mention a chewable tablet comprising a particulate material for controlled release of an active ingredient, the particulate material comprising a combination of one or more active ingredients and an inorganic mineral filler, wherein the active ingredient Reversibly absorbed into the inorganic mineral filler and/or adsorbed onto the inorganic mineral filler, and wherein the inorganic mineral filler has a BET specific surface area exceeding 15 m ² /g. However, no mention is made of methods or other components for improving the protection of the active ingredient or for improving or controlling the release characteristics of the carrier. In contrast, the release of the active ingredient is essentially achieved by chewing (i.e., mechanically) and not due to a particular composition.

Carriers which provide excellent controlled release properties are known, for example, from EP 2 168 572 and are based on surface-reacted calcium carbonate. The results indicate that it is advantageous to use a surface-reacted calcium carbonate as a carrier for the active agent, for example, for applications requiring a high load to sustain a "slow release effect." In this regard, the porous structure of the surface reacted calcium carbonate is destined to significantly absorb polar and non-polar fluids.

Therefore, only the low-load release is provided when it is in the form of pellets. The porous structure of the surface-reacted calcium carbonate provides a high load-prolonging release effect compared to ground calcium carbonate (GCC). This is essentially due to the fact that the pore volume within the particles of the surface reacted calcium carbonate is much larger than the interparticle only volume of GCC.

According to EP 2 168 572, it has now been found that surface-reacted calcium carbonate particles not only provide excellent controlled release properties, but also have a thermal insulating effect which can be improved even by encapsulation of a surface-reacted calcium carbonate-based support.

Furthermore, the results indicate that encapsulation of the support by means of a coating covering the surface of the surface of the reacted calcium carbonate support significantly improves the protective properties of the support relative to the active agent to be released, and allows for even more precise control depending on environmental conditions. The active agent is released.

Thus, according to the present invention, the above problems have been solved by a carrier for controlled release of an active agent comprising: a core comprising - surface-reacted natural or synthetic calcium carbonate, and - at least one active agent, wherein the at least one active The agent is associated with the surface by reacting natural or synthetic calcium carbonate, and wherein the surface is reacted with natural or synthetic calcium carbonate as a reaction product of natural or synthetic calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is treated with an acid The bit is formed and/or supplied by an external source, and - the coating of the core is encapsulated.

The core of the carrier of the present invention comprises a surface-reacted natural or synthetic calcium carbonate, wherein the preferred synthetic calcium carbonate is precipitated calcium carbonate (PCC) selected from the group consisting of A group of aragonite-type, vaterite-type or calcite-type mineral crystal forms or mixtures thereof.

The natural calcium carbonate is preferably selected from the group consisting of calcium carbonate-containing minerals selected from the group consisting of marble, chalk, calcite, dolomite, limestone, and mixtures thereof.

In a preferred embodiment, the natural or synthetic calcium carbonate is ground prior to treatment with one or more acids and carbon dioxide. The milling step can be carried out using any of the conventional grinding devices known to those skilled in the art, such as a grinder.

The surface to be used in the present invention may be in solid form by reaction with natural or synthetic calcium carbonate, but is preferably provided in the form of an aqueous suspension which has a pH of greater than 6.0, preferably greater than 6.5, measured at 20 ° C. More preferably greater than 7.0, and even more preferably greater than 7.5.

In a preferred method of preparing an aqueous suspension, the natural and synthetic calcium carbonate is finely comminuted (such as by milling) or suspended in water without fine comminution. Preferably, the slurry has a natural or synthetic calcium carbonate content ranging from 1 wt% to 80 wt%, more preferably from 3 wt% to 60 wt%, and even more preferably from 5 wt% to 40 wt%, based on the weight of the slurry.

In the next step, an acid is added (in the context of the present invention it is a Bronsted acid (Br) Nsted acid), that is, H ₃ O ⁺ ion donor) to an aqueous suspension containing natural or synthetic calcium carbonate. Preferably, pK _a of the acid at 25 deg.] C of 2.5 or less than 2.5. If the pK _a at 25 deg.] C is 0 or less than 0, preferably selected from sulfuric acid, hydrochloric acid or mixtures thereof. If the pK _a at 25 deg.] C is from 0 to 2.5, the acid is preferably selected from ^{_{H 2 SO 3, M + HSO}} 4 - (M + is selected from the group comprising sodium and potassium alkali metal ions), H ₃ PO ₄ , oxalic acid or a mixture thereof.

One or more acids may be added to the suspension as a concentrated solution or as a dilute solution. Preferably, the molar ratio of acid to natural or synthetic calcium carbonate is from 0.05 to 4, more preferably from 0.1 to 2.

Alternatively, it is also possible to add the acid to the water before suspending the natural or synthetic calcium carbonate.

In the next step, natural or synthetic calcium carbonate is treated with carbon dioxide. If a strong acid such as sulfuric acid or hydrochloric acid is used in the acid treatment of natural or synthetic calcium carbonate, carbon dioxide is automatically formed. Alternatively or additionally, carbon dioxide may be supplied from an external source.

The acid treatment can be carried out simultaneously with the treatment with carbon dioxide, which is the case when a strong acid is used. It is also possible to first carry out an acid treatment, for example with pK _a in the range of 0 to 2.5, followed by treatment with carbon dioxide supplied from an external source.

Preferably, the concentration of gaseous carbon dioxide in the suspension is in terms of volume such that the ratio (volume of suspension): (volume of gaseous CO ₂ ) is from 1:0.05 to 1:20, even more preferably from 1:0.05 to 1:5.

In a preferred embodiment, the acid treatment step and/or the carbon dioxide treatment step are repeated at least once, more preferably several times.

After the acid treatment and the carbon dioxide treatment, the pH of the aqueous suspension is measured at 20 ° C to naturally reach a value of more than 6.0, preferably more than 6.5, more preferably more than 7.0, even more preferably more than 7.5, thereby preparing a pH value. The surface of the aqueous suspension in the form of greater than 6.0, preferably greater than 6.5, more preferably greater than 7.0, even more preferably greater than 7.5, is reacted with natural or synthetic calcium carbonate. If the aqueous suspension is brought to equilibrium, the pH is greater than 7. When the aqueous suspension is stirred for a sufficient period of time, preferably from 1 hour to 10 hours, more preferably from 1 to 5 hours, without adding The pH value greater than 6.0 was adjusted with the addition of a base.

Alternatively, the pH of the aqueous suspension can be increased to a value greater than 6 by adding a base after carbon dioxide treatment before reaching equilibrium (which occurs when the pH is greater than 7). Any conventional base such as sodium hydroxide or potassium hydroxide can be used.

Further details regarding the preparation of surface-reacted natural calcium carbonate are disclosed in WO 00/39222, WO 2004/083316, WO 2005/121257, WO 2009/074492, EP 2 264 108 A1, EP 2 264 109 A1 and US 2004/0020410 In A1, wherein the surface-reacted natural calcium carbonate is described as a filler for papermaking, the contents of such references are incorporated herein by reference.

The surface-reacted calcium carbonate suitable for use in the present invention can also be prepared by contacting ground natural calcium carbonate with at least one water-soluble acid and gaseous CO ₂ , wherein the pK _{a of the} acid or the acid is measured at 20 ° C It is greater than 2.5 and less than or equal to 7, which is related to the ionization of the hydrogen which is first obtainable, and the corresponding anion formed upon the loss of hydrogen which is first obtainable is capable of forming a water-soluble calcium salt. Subsequently, additionally providing at least one water-soluble salt having a pK _a of greater than 7 in the case of a hydrogen-containing salt when measured at 20 ℃ at which ionization of the first available hydrogen related and which anion is capable of forming salts Water insoluble calcium salt.

In this regard, exemplary acids are acetic acid, formic acid, propionic acid, and mixtures thereof, and exemplary cations of the water-soluble salt are selected from the group consisting of potassium, sodium, lithium, and mixtures thereof, and examples of such water-soluble salts The anionic group is selected from the group consisting of phosphate, dihydrogen phosphate, monohydrogen phosphate, oxalate, citrate, mixtures thereof, and hydrates thereof.

Further details regarding the preparation of such surface-reacted natural calcium carbonates are disclosed in EP 2 264 108 A1 and EP 2 264 109 A1, the contents of which are hereby incorporated by reference.

Similarly, the surface was subjected to reaction precipitation of calcium carbonate. As is known in detail from EP 2 070 991, surface-reacted precipitated calcium carbonate is obtained by contacting precipitated calcium carbonate with H ₃ O ⁺ ions in an aqueous medium and with anions dissolved in an aqueous medium and capable of forming a water-insoluble calcium salt. Obtained by forming a slurry of surface-reacted precipitated calcium carbonate, wherein the surface-reacted precipitated calcium carbonate comprises an insoluble at least partially crystalline calcium salt of the anion formed on the surface of at least partially precipitated calcium carbonate.

The dissolved calcium ions correspond to dissolved calcium ions which are naturally dissolved in excess of dissolved calcium ions by precipitation of precipitated calcium carbonate by H ₃ O ⁺ ions, wherein the H ₃ O ⁺ ions are only in the form of relative ions of anions (ie, via the addition of an anion in the form of an acid or a non-calcium salt), and there are no other sources of calcium or calcium ion production.

The excess dissolved calcium ions are preferably provided by the addition of a soluble Chinese or acidic calcium salt or by the addition of an acid or a Chinese or acid non-calcium salt which produces a soluble Chinese or acidic calcium salt in situ.

The H ₃ O ⁺ ions may be provided by the addition of an acid or acid salt of the anion or by addition of an acid or acid salt which is used to provide all or part of such excess dissolved calcium ions.

In a preferred embodiment of the preparation of the surface-reacted natural or synthetic calcium carbonate, the natural or synthetic calcium carbonate is reacted with an acid and/or carbon dioxide in the presence of at least one compound selected from the group consisting of citrate, oxygen Huayu, aluminum hydroxide, alkaline earth aluminate (such as sodium aluminate or potassium aluminate), magnesium oxide or a mixture thereof. Preferably, the at least one citrate is selected from the group consisting of aluminum citrate, calcium citrate or alkaline earth metal citrate. These components can be added to an aqueous suspension comprising natural or synthetic calcium carbonate prior to the addition of acid and/or carbon dioxide.

Alternatively, the citrate and/or cerium oxide and/or aluminum hydroxide and/or alkaline earth aluminate and/or magnesium oxide components may be added to the reaction of the natural or synthetic calcium carbonate with the acid and carbon dioxide at the beginning. In aqueous suspensions of natural or synthetic calcium carbonate. Further details regarding the preparation of surface-reacted natural or synthetic calcium carbonate in the presence of at least one silicate and/or cerium oxide and/or aluminum hydroxide and/or alkaline earth aluminate component are disclosed in WO 2004/083316 The contents of this reference are hereby incorporated by reference.

The surface-reacted natural or synthetic calcium carbonate can be maintained in the suspension and further stabilized by a dispersing agent as appropriate. Known dispersing agents known to those skilled in the art can be used. A preferred dispersant is polyacrylic acid.

Alternatively, the above aqueous suspension may be dried to obtain a surface-reacted natural or synthetic calcium carbonate in the form of a solid in the form of granules or powder (i.e., dried or containing very little water which is not in fluid form).

In a preferred embodiment, the surface-reacted natural or synthetic calcium carbonate has a specific surface area of from 5 m ² /g to 200 m ² /g, more preferably 20 m ² / measured according to ISO 9277 using nitrogen and BET methods. g to 80 m ² /g and even more preferably from 30 m ² /g to 60 m ² /g.

Further, the weight of the preferred surface-reacted natural or synthetic calcium carbonate is preferably from 0.1 to 50 μm, more preferably from 0.5 to 25 μm, especially from 0.8 to 20 μm, most preferably from 1 to 10 μm, as measured by sedimentation. The settlement method is an analysis of the settlement behavior in the gravity field. Using Sedigraph ^TM 5100 Micromeritics Instrument Company for measuring natural calcium carbonate. Methods and apparatus are known to those skilled in the art and are commonly used to determine the particle size of fillers and pigments. The measurement was carried out in a 0.1 wt% aqueous solution of Na ₄ P ₂ O ₇ . The sample was dispersed using a high speed agitator and subjected to ultrasonic treatment.

The weight median particle diameter of the surface reacted calcium carbonate (MCC) was determined by using a Malvern Mastersizer 2000 laser diffraction system known to those skilled in the art.

In a preferred embodiment, the surface-reacted natural or synthetic calcium carbonate has a specific surface area in the range of 5 to 200 m ² /g and a weight median particle diameter in the range of 0.1 to 50 μm. More preferably, the specific surface area is in the range of 20 to 80 m ² /g and the weight median particle diameter is in the range of 0.5 to 25 μm. Even more preferably, the specific surface area is in the range of 30 to 60 m ² /g and the weight median particle diameter is in the range of 0.7 to 7 μm.

The surface-reacted calcium carrier is capable of concomitantly transporting the active agent. The association is based on adsorption to the surface of the surface of the reacted calcium carbonate particles (whether on the outer or inner surface of the particles) and adsorption and/or absorption into the pores of the particles. As mentioned above and in EP 2 168 572, the intra- and inter-porous structures of the reacted calcium carbonate on the surface of the salty surface provide adsorption and/or absorption characteristics superior to conventional materials having similar specific surface areas. Thus, the basic adsorption and/or absorption characteristics for a given agent can be controlled by pore size and/or pore volume and/or surface area.

Preferably, the porosity of the surface-reacted natural or synthetic calcium carbonate particles is from 5 vol% (v/v) to 50 vol% (v/v), preferably from the mercury porosimetry measurement. 20 vol% (v/v) to 50 vol% (v/v), especially 30 vol% (v/v) to 50 vol% (v/v). In the bimodal derived pore size distribution curve, the lowest point between the peaks indicates the diameter of the pore volume between the particles and the particles. The pore volume larger than the diameter of the diameter is the pore volume associated with the pores between the particles. The total pore volume minus the pore volume between the particles obtains the pore volume within the particle, and the pore volume within the particle can be calculated as a fraction of the solid material volume as described in Transport in Porous Media (2006) 63:239-259. Porosity.

Therefore, the inter-particle porosity measured in the form of pore volume per unit particle volume is calculated from the mercury porosimetry measurement, and is between 20 vol% (v/v) and 99 vol% (v/v). Good 30 vol% (v/v) to 70 vol% (v/v), better 40 vol% (v/v) to 60 vol% (v/v), for example 50 vol% (v/v) ).

As already mentioned, the adsorption and/or absorption and release of the active agent is substantially controlled by the pore size, as determined by mercury porosimetry, preferably in the range of 10 to 100 nm, more preferably In the range between 20 nm and 80 nm, especially 30 to 70 nm, for example 50 nm.

Thus, in general, any agent that conforms to intraparticle and/or interparticle pores of the surface reacted calcium carbonate support is suitable for transport by the surface of the present invention via a reaction calcium carbonate carrier.

Within this scope, any active agent (whether in industry, agriculture or any other application, such as for transport or delivery to a human or animal body in a human or animal body) may be suitable for use in the present invention, for example selected from the group consisting of Group of agents: anti-microbial, pharmaceutical, biological, cosmetic active agents, nutrition (eg vitamins), salts, adjuvants (such as caffeine and guarana), and health-promoting bacteria (such as probiotics), flavoring or flavoring agents, biocides, fungicides, insecticides or Herbicides and disinfectants.

More preferably, the active agent from the group of active agents mentioned in the Biocidal Products Directive 98/8/EC (BPD), preferably of the product type (PT) 1-23, more preferably PT6 and 12, the best is PT6-13.

For example, an active agent such as selected from the group consisting of glutaraldehyde (GDA), isothiazolinone (such as 2-methyl-2H-isothiazol-3-one (MIT), 5-chloro) may be used. -2-methyl-2H-isothiazol-3-one (CMIT), benzisothiazolinone (BIT), octyl-isothiazolinone (OIT), 4,5-dichloro-2-n-octyl 4-isothiazol-3-one (DCOIT)), 2-bromo-2-nitro-1,3-propanediol (Bronopol), 2,2-dibromo-3-nitropropyl Indoleamine (DBNPA), o-phenylphenol (OPP) and its salts, phenoxyethanol, formaldehyde, ethylene glycol hemiacetal, 1-(3-chloroallyl)-3,5,7-three Aza-1-azapurine adamantane chloride, barium hydroxymethyl hydrazine (THPS), 4,4-dimethyloxazolidine (DMO), hexahydro-1,3,5-gin (2-hydroxyl Ethyl)-s-triazine, hexahydro-1,3,5-triethyl-s-triazine (HTT), tetrahydro-3,5-dimethyl-2H-1,3,5-thia Diazine-2-thione (DAZOMET), 3-iodo-2-propynylcarbamic acid butyl ester (IPBC), 5-chloro-2-(2,4-dichlorophenoxy)-phenol (three Triclosan); and its derivatives, salts and mixtures; anticarcinogens, limonene, peppermint, surfactants (such as defoamers or softeners), mineral oils, strontiums, wetting agents, waxes, stones Hydrolysis agents (such as hydrolysis binder) and an anti-dust oil.

In a preferred embodiment, glutaraldehyde, bronopol, isothiazoline are used. Ketones (such as MIT, CMIT, BIT, OIT) and mixtures thereof.

For example, a mixture of glutaraldehyde and CMIT/MIT in a weight ratio of about 23.5:1.05:0.35 can be used.

In a preferred embodiment of the invention, the core comprising the surface reacted calcium carbonate and at least one active agent is in the form of a troche, pellet, granule or powder.

As mentioned above, the results indicate that the carrier properties can be significantly improved by combining the surface of the active agent loaded with the active calcium carbonate as described above with the coating, for example in the protection of the active agent in a hazardous environment and in the release Features and control aspects.

The coating material which can be advantageously used in the present invention is selected from the group consisting of water-soluble polymers and water-insoluble polymers selected from the group consisting of methyl cellulose, hydroxypropyl cellulose, and hydroxy group. Propylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, pullulan, tragacanth, guar gum ), acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, amylose, high amylose, hydroxypropylated high amylose, dextrin, Pectin, chitin, polyglucamine, gelatin, zein, gluten, isolated soy protein, isolated whey protein, casein and derivatives, salts and mixtures thereof; and the water insoluble polymers are selected from the group consisting of Group: hydrogenated vegetable oil, hydrogenated castor oil, polyvinyl chloride, shellac, polyurethane, cellulose derivatives, rosin, wood rosin, wax, acrylate and methacrylate polymers, copolymerization of acrylic acid and methacrylate And derivatives, salts and mixed Compound.

The release and protection properties are tailored by proper selection of the appropriate coating, visible active agent and release environment.

For example, in a preferred embodiment of the invention, the protection and controlled release of the thermosensitive antimicrobial agent can be suitably controlled, for example, by the use of a methylcellulose coating which is particularly suitable for industrial applications.

Therefore, in a particularly preferred embodiment, the coating material is methylcellulose.

Moreover, it is generally possible to combine the carriers of the present invention with other materials to form suitable formulations for corresponding applications. It can be included, for example, in capsules, lozenges, creams, and the like. In addition, it is possible to use surface-reacted calcium carbonate suspended in water, an oil such as a mineral oil fraction or a vegetable oil such as jojoba oil or an alcohol such as ethanol.

However, for oral applications, particularly where the release of the active agent is substantially based on mechanical release, it is preferred that the carrier of the present invention is not used in the form of a formulation, such as in the form of a chewable tablet formulation.

As can be seen from the above, the surface-reacted calcium carbonate carrier is suitable for transporting various agents associated therewith.

The loaded core may further comprise a conventional amount of a conventional galenical additive such as a lubricant, a disintegrant, a binder, an antioxidant, a pH adjuster, a colorant, a flavoring agent, a stabilizer, and the like.

For example, it may be suitable to add a lubricant (such as magnesium stearate) in an amount of 0.1 to 5 wt%, preferably 0.5 to 3 wt%, more preferably 1 to 2 wt%, based on the weight of the reaction calcium carbonate.

In some embodiments, for example, the surface is reacted with calcium carbonate. Disintegrating agents such as sodium carboxymethylcellulose in an amount of from 0.5 to 10% by weight, preferably from 3 to 8% by weight, more preferably from 5 to 6% by weight, are also advantageous.

The carrier of the present invention can be produced by a process comprising the steps of: providing a surface-reacted calcium carbonate, providing an active agent in the form of a solution or suspension in a suitable medium, - reacting the surface with reacted calcium carbonate and an active agent Contacting - separating the supported surface from the reaction of the calcium carbonate with excess liquid, solution or suspension - coating the separated supported surface reacted calcium carbonate with a coating material.

The association is usually achieved by contacting the surface with a solution or suspension of the active agent in a suitable medium (i.e., adsorption and/or absorption of the agent onto the surface of the reacted calcium carbonate support and/or into it), The suitable medium is preferably water but can generally be any medium. However, if the medium is acidic, it needs to be weaker and less dilute than the acid forming the salt of the reaction surface. It can then be exposed to a lower pH for at least a limited time.

The surface-reacted calcium carbonate can be provided, for example, in the form of a troche, pellet, granule or powder, which is separated from the excess liquid, solution or suspension, for example by filtration, and optionally dried, after the association step.

It is also possible to provide the surface reacted calcium carbonate in powder form, in contact with the active agent, and subsequently, prior to coating, into a form, such as a lozenge or pill, using methods well known in the art for this purpose. Or particles.

Drying is preferably carried out by well controlled drying methods such as mild spray drying or oven drying.

Subsequently, by methods well known in the art (eg, in a fluidized bed) Form) coating the surface of the reacted calcium carbonate core with at least one active agent associated therewith with a coating material.

The resulting coated carrier can be applied directly or included in a formulation as described above (such as a cream, lozenge, capsule or any other formulation suitable for the corresponding application).

As indicated above, the vectors of the present invention have a number of advantages and are particularly useful for transporting active agents to a target environment and for controlled release of active agents.

It can be used in many fields such as paper, paint, paint, pharmaceutical, biological, cosmetic, industrial, such as water purification or agricultural applications.

However, for oral applications, particularly where the release of the active agent is substantially based on mechanical release, it may be preferred to exclude use in the form of a formulation, such as in the form of a chewable tablet formulation.

The carrier may be particularly suitable for the delivery and controlled release of heat sensitive active agents. In the context of the present invention, a "heat sensitive" active agent means a compound which is chemically converted by loss of its activity or even thermal degradation by exposure to heat.

In addition, the results show that by selecting a suitable coating, not only is the active agent well protected, for example, not degraded by excess heat, but it is even possible to have temperature-dependent controlled release.

For example, most industrially applied antimicrobial agents have limited temperature stability and degrade at temperatures in excess of 50 °C.

Loaded with a heat sensitive active agent (such as an antimicrobial agent (such as glutaraldehyde), bronopol, isothiazolinone (such as MIT, CMIT, BIT, OIT) and mixtures thereof) and coated with methylcellulose surface Reaction of calcium carbonate The combination prevents degradation of the active agent at temperatures up to 80 °C.

Thermal protection can generally be achieved at up to 60 ° C, preferably up to 80 ° C, more preferably up to 100 ° C, optimally up to 150 ° C.

According to the invention, thermal protection is achieved for at least some minutes (such as 15 minutes or 30 minutes), to most hours (such as 2 to 12 hours, preferably at most 4 to 9 hours, such as 6 hours) and ideally for up to 1 to 3 days. Or even longer, it is advantageous.

In the context of the present invention, thermal protection means that the heat sensitive active agent still has its desired activity after exposure to heat in the target environment.

Thus, the use of a surface delivery reaction of calcium carbonate as an absorbent and an active agent (e.g., an antimicrobial agent) is beneficial for applications that require a high load to sustain a "slow release effect." By combining with a coating such as a methylcellulose coating, it is possible to protect, for example, a heat sensitive active agent, such as an antimicrobial agent, to provide controlled release of the active agent at a temperature that maximizes sustainability.

These discovered industrial applications contribute to more effective protection of the environment and financial resources and reveal the basic principles of alternative protection strategies.

Accordingly, the present invention is also directed to a method for delivering an active agent to a target environment and/or for controlled release, preferably a temperature controlled release active agent, preferably a heat sensitive active agent, and a method of using the invention as defined above A method of protecting a heat sensitive active agent by a carrier.

The invention is illustrated by the following figures, examples and tests, but is not intended to limit the invention in any way.

Example

To evaluate the thermal protection effect of the carrier of the present invention, two samples were prepared, coated samples and uncoated samples for comparison reasons.

Measurement method

The parameters given in the examples and the scope of the patent application were evaluated using the following measurement methods.

BET specific surface area of the material

After adjusting the sample by heating at 250 ° C for a period of 30 minutes, the BET specific surface area was measured using a nitrogen gas according to ISO 9277 via the BET method. Prior to such measurements, the samples were filtered, rinsed and dried in an oven at 110 °C for at least 12 hours.

Particle size distribution of particle material (% by mass of particles < diameter X) and weight median diameter ( d ₅₀ ):

The weight median particle diameter and particle diameter mass distribution of the particle material are determined by a sinking method (ie, analyzing the settling behavior in the gravitational field). Measurement was carried out with a Sedigraph ^TM 5100.

The weight median particle diameter of the surface reacted calcium carbonate was determined by using a Malvern Mastersizer 2000 laser diffraction system.

Methods and apparatus are known to those skilled in the art and are commonly used to determine the particle size of fillers and pigments. The measurement was carried out in a 0.1 wt% aqueous solution of Na ₄ P ₂ O ₇ . The sample was dispersed using a high speed agitator and ultrasonic waves.

HPLC analysis

HPLC analysis was performed on a Waters 600 system (Waters AG, 5405 Baden-Dättwil, Switzerland) equipped with an on-line degassing apparatus equipped with a 717 plus autosampler and a 2996 photodiode array detector. A 250 x 4.6 mm Nucleosil 120-5 C18 column (4702 Oensingen, Switzerland) from Macherey-Nagel Corporation was used.

HPLC parameters:

Eluent Water: Methanol; 70:30 v/v

Flow rate: 1 ml / min

Injection volume: 10 μl

Wavelength: 275 nm

Temperature: 30 ° C

2. Carrier preparation

The pore structure of the surface reacted calcium carbonate was determined by the amount of mercury in the dried surface of the reacted calcium carbonate powder using a Micromeritics Autopore IV mercury porosimeter and compared to compacted GCC samples (pellets). The maximum mercury pressure applied is 414 MPa, which is equivalent to a Laplace throat diameter of 4 nm. The measured amount of mercury has been corrected for the compression of mercury, the expansion of the penetrator, and the compressibility of the solid phase of the sample. This is done using the software Pore-Cor (Gane, PAC, Kettle, JP, Matthews, GP and Ridgway, CJ, (1996) Void Space Structure of Compressible Polymer Spheres and Consolidated Calcium Carbonate Paper-Coating Formulations, Ind. Eng. Chem. Res., 35(5), 1753-1764; Pore-Cor is a software suite with the Environmental and Fluid Modelling Group, University of Plymouth, PL4 8AA, UK).

2a, b and c illustrate the porosity of the surface-reacted calcium carbonate (SRCC) and the known GCC used in the present invention, as well as the pore size distribution and pores thereof. Path distribution. The mercury intrusion curve of the surface-reacted calcium carbonate is divided into separated bimodal particles and intra-particle size regions. From this measurement, the total porosity is 83 vol% (v/v), the interparticle porosity is 48 vol% (v/v), and the intraparticle porosity is 35 vol% (v/v). Compressed GCC provides only a pellet porosity of 29 vol% (v/v).

a) Formulation of unreacted surface-calculated calcium carbonate core:

The surface was reacted with calcium carbonate and 1 wt% magnesium stearate (CAS No. 557-04-0) and 5 wt% carboxymethylcellulose on the surface of the reaction calcium carbonate by a Turbula mixer at room temperature. Sodium (CAS No. 9004-32-4) was thoroughly mixed for about 30 minutes and then pelletized using an eccentric press Korsch Pressen EKO (Korsch AG) using a 6 mm diameter punch. Adjust the compression parameters to a fill depth of 9 mm and a hardness of 6.

The quality of the obtained pellets was tested by using a rupture strength test and a disintegration test of Pharma Test Typ PTB (Pharma Test Apparate Bau AG). To test the disintegration characteristics, the pelletized core was dried to constant weight at 150 ° C using a moisture analyzer MJ33 prior to taring. The core was tested for disintegration for 30 minutes in 100 ml of deionized water and Hydrocarb 90 with stirring at 200 rpm. Capsule residues larger than 45 μm were collected with a sieve, dried to constant weight at 150 ° C and evaluated gravimetrically.

b) association of active agents

Subsequently, 0.5 wt% of an aqueous solution of 2-methyl-2H-isothiazol-3-one (MIT) (20 wt% MIT by weight of the surface treated calcium carbonate) was transferred to 10 by pipetting. The surface of the g-calcined calcium carbonate core allows the unsupported surface to be supported by the reacted calcium carbonate core. In order to distribute the active agent evenly, The core was mixed in a closed container for 2 days with a roller mixer.

c) coating

Methocel A4M 4000 mPa ‧ (methyl cellulose available from Dow, CAS No. 9004-67-5) was used to encapsulate the resulting loaded core. Methylcellulose rapidly expands in cold water and can produce agglomerates. Thus, a dispersion of 2 wt% of methylcellulose in hot water was prepared. Methylcellulose dissolves during cooling. The loaded core of step b) was immersed in 50 ml of 2 wt% methylcellulose dispersion for 15 minutes at 20 ° C and dried at room temperature for two days. The coating procedure was repeated three times.

3. Results Release behavior

Figure 3 shows the temperature dependence of the methylcellulose A4M coated core and uncoated cores as determined by MIT as described above by HPLC after 4 hours at 80 ° C and 20 ° C in 100 ml of deionized water. Sexual release rate. It is apparent that at higher temperatures methylcellulose is able to maintain MIT within the porous structure of the MCC, and then diffusion (release) can occur at lower temperatures.

Figures 1a and 1b show SEM images of surface-reacted calcium carbonate (Figure 1a) and conventional GCC (Figure 1b) suitable for use in the present invention.

Figures 2a, b and c show graphs illustrating the porosity of the surface reacted calcium carbonate (SRCC) and known GCC of the present invention, as well as its differential pore size distribution and pore size distribution.

Figure 3 shows the coated and uncoated carrier at different temperatures 4 Diagram of release characteristics (in ppm) after hours.

Claims (42)

A carrier for controlled release of an active agent, comprising: a core comprising: surface reacted natural or synthetic calcium carbonate, and at least one active agent, wherein the at least one active agent Associated with the surface reacted with natural or synthetic calcium carbonate, and wherein the surface is reacted with natural or synthetic calcium carbonate as a reaction product of natural or synthetic calcium carbonate with carbon dioxide and one or more acids, wherein the carbon dioxide is The acid treatment is formed in situ and/or supplied by an external source, and - the coating of the core is encapsulated. The carrier according to claim 1, characterized in that the surface is in the form of a solid by reaction of natural or synthetic calcium carbonate or an aqueous suspension comprising the surface of the reacted calcium carbonate and having a pH of more than 6.0 at 20 ° C. form. The carrier of claim 1, wherein the natural calcium carbonate is selected from the group consisting of calcium carbonate-containing minerals selected from the group consisting of marble, calcite, chalk, dolomite, limestone, and mixtures thereof. A carrier according to claim 2, characterized in that the natural calcium carbonate is selected from the group consisting of calcium carbonate-containing minerals selected from the group consisting of marble, calcite, chalk, dolomite, limestone and mixtures thereof. A carrier according to claim 1, characterized in that the synthetic calcium carbonate is a precipitated calcium carbonate selected from the group consisting of aragonitic, vateritic or calitic mineral crystals ( Mineralogical crystal form) or a mixture thereof. A carrier according to claim 2, characterized in that the synthetic calcium carbonate is a precipitated calcium carbonate selected from the group consisting of aragonite type, vaterite type or calcite type mineral crystal form or a mixture thereof. A carrier according to claim 1 or 2, characterized in that the surface-reacted natural or synthetic calcium carbonate has a specific surface area of from 5 m ² /g to 200 m ² /g according to ISO 9277 using a nitrogen gas and a BET method. A carrier according to claim 1 or 2, characterized in that the weight median particle diameter d ₅₀ of the surface-reacted natural or synthetic calcium carbonate is 0.1 to 50 μm according to a sedimentation method. A carrier according to claim 1 or 2, characterized in that it is calculated from a mercury porosimetry measurement, and the porosity of the surface of the surface of the reacted natural or synthetic calcium carbonate is 5 vol% (v/v) to 50 vol% (v/v). A carrier according to claim 1 or 2, characterized in that the at least one active agent is adsorbed onto the surface-reacted calcium carbonate particles or absorbed into the surface-reacted calcium carbonate particles or both. The carrier according to claim 1 or 2, wherein the at least one active agent is selected from the group consisting of an antimicrobial active agent, a pharmaceutically active agent, a biological active agent, a cosmetic active agent, and a nutrition. A substance, a salt, a booster, a health promoting bacteria, a scented agent, a flavoring agent, a biocide, a fungicide, an insecticide, a herbicide, and a disinfectant. A carrier according to claim 1 or 2, characterized in that the at least one active agent is selected from the group of active agents mentioned in Biocidal Products Directive 98/8/EC (BPD). A carrier according to claim 1 or 2, characterized in that the at least one active agent is selected from the group consisting of glutardialdehyde (GDA), isothiazlinone, 2- Bromo-2-nitro-1,3-propanediol (Bronopol), 2,2-dibromo-3-nitropropionamide (DBNPA), o-phenylphenol (OPP) and salts thereof, Phenoxyethanol, formaldehyde, ethylene glycol hemiacetal, 1-(3-chloroallyl)-3,5,7-triaza-1-azonazepine adamantane chloride, barium sulfate Hydroxymethyl hydrazine (THPS), 4,4-dimethyloxazolidine (DMO), hexahydro-1,3,5-paraxyl (2-hydroxyethyl)-s-triazine (triazine), hexahydrogen -1,3,5-triethyl-s-triazine (HTT), tetrahydro-3,5-dimethyl-2H-1,3,5-thiadiazine-2-thione (DAZOMET), 3-iodo-2-propynylcarbamic acid butyl ester (IPBC), 5-chloro-2-(2,4-dichlorophenoxy)-phenol (triclosan); and derivatives thereof , salts and mixtures; anticarcinogens, limonene, peppermint, surfactants, mineral oils, hydrazines, wetting agents, waxes, paraffins, hydrolyzing agents and anti-dust oils. A carrier according to claim 1 or 2, characterized in that the core comprising surface-reacted calcium carbonate and at least one active agent is in the form of a troche, pellet, granule or powder. The carrier according to claim 1 or 2, wherein the coating material is selected from the group consisting of a water-soluble polymer and a water-insoluble polymer, the water-soluble polymer being selected from the group consisting of methyl groups: methyl group Cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, sodium alginate, polyethylene glycol, pullulan, Astragalus gum, guar gum, acacia gum, arabic gum, polyacrylic acid, methyl methacrylate copolymer, carboxyvinyl polymer, amylose, high amylose, Hydroxypropylated high amylose, dextrin, pectin, chitin, polyglucamine, gelatin, zein, gluten, isolated soy protein, isolated whey protein, casein, and derivatives, salts and mixtures thereof; And the water-insoluble polymer is selected from the group consisting of hydrogenated vegetable oil, hydrogenated castor oil, polyvinyl chloride, shellac, polyurethane, cellulose derivative, rosin gum, wood rosens, wax, acrylate Methyl propylene Ester polymers, copolymers of acrylic acid and methyl acrylate, and derivatives, salts and mixtures thereof. For example, the carrier of claim 1 or 2 is used in paper, paint, coating, pharmaceutical, biological, cosmetic or agricultural applications. A carrier according to claim 11 is characterized in that the nutrient is a vitamin. A carrier according to claim 11 which is characterized in that the adjuvant is caffeine or guarana. A carrier according to claim 11 is characterized in that the health promoting bacteria are probiotics. A carrier according to claim 12, characterized in that the at least one active agent is selected from the group consisting of product types (PT) 1-23. A carrier according to claim 12, characterized in that the at least one active agent is selected from the group consisting of PT6 and 12. A carrier according to claim 12, characterized in that the at least one active agent is selected from the group consisting of PT6-13. The carrier according to claim 13 is characterized in that the isothiazolinone is 2-methyl-2H-isothiazol-3-one (MIT), 5-chloro-2-methyl-2H-isothiazole- 3-ketone (CMIT), benzisothiazolinone (BIT), octyl-isothiazolinone (OIT) or 4,5-dichloro-2-n-octyl-4-isothiazol-3-one ( DCOIT). A carrier according to claim 13 which is characterized in that the surfactant is an antifoaming agent or a softening agent. A carrier according to claim 13 which is characterized in that the hydrolyzing agent is a hydrolyzable binder. A process for the preparation of a carrier according to any one of claims 1 to 25, characterized in that the step of providing the surface-reacted calcium carbonate is provided in the form of a solution or suspension in a suitable medium. The active agent; - contacting the surface with the reacted calcium carbonate with the active agent, - separating the supported surface from the reaction liquid calcium carbonate with excess liquid, solution or suspension - coating the separated process with the coating material The surface of the load is reacted with calcium carbonate. Use of a carrier according to any one of claims 1 to 25 for use in paper, paint, paint, cosmetic, industrial or agricultural applications. A use of a carrier according to any one of claims 1 to 25 for delivering an active agent to a target environment, wherein the target environment is not a living human or animal. Use of a carrier according to any one of claims 1 to 25 for a controlled release active agent, wherein the active agent is not administered to a living human or animal. The use of any one of the 28th or 29th aspect of the invention is characterized in that the active agent is heat sensitive. The use of the scope of claim 29 is characterized in that the controlled release is temperature controlled. The use of the scope of claim 30 is characterized in that the controlled release is temperature controlled. A use of a carrier according to any one of claims 1 to 25 for protecting a heat sensitive active agent. A method of delivering an active agent to a target environment using a carrier according to any one of claims 1 to 25, wherein the target environment is not a living human or animal. A method of controlled release of an active agent, which comprises the use of a carrier according to any one of claims 1 to 25, wherein the active agent is not administered to a living human or animal. The method of any one of claims 34 or 35, wherein the active agent is heat sensitive. The method of claim 35, wherein the controlled release is temperature controlled. The method of claim 36, wherein the controlled release is temperature controlled. A method of protecting a heat-sensitive active agent using a carrier according to any one of claims 1 to 25. A use of a carrier according to any one of claims 1 to 25 for the preparation of a medicinal or biologically acceptable pharmaceutical. Use of a carrier according to any one of claims 1 to 25 for the preparation of a medicament, wherein the carrier delivers the active agent to a living human or animal. A use of a carrier according to any one of claims 1 to 25 for the preparation of a controlled release pharmaceutical product, wherein the pharmaceutical product is administered to a living human or animal.